Brain edema (cytotoxic and vasogenic edema) and secondary brain injury are the major responses of the central nervous system to heterogenous primary pathological disorders including ischemia, trauma and hypoxia. The fundamental mechanisms of the edema development and neuronal injury following ischemia and trauma are major subjects of this research proposal. We will focus primarily on glutamate receptor (NMDA and non-NMDA), second messenger system (arachidonic acid, 1,4,5-inositol triphosphate), injury markers (heat shock proteins) and factors (oxygen radicals) that are associated with cellular swelling, membrane injury and cell death following cerebral ischemia and hypoxia. The factors generated by trauma and hypoxia that increase blood-brain barrier permeability and the subsequent development of vasogenic edema will be fully investigated. Thus the research projects of the CNS Injury and Edema Center provide for interdisciplinary studies ranging from the biochemical, physiological, and ultrastructural basis of various types of brain edema and neuronal injury to pharmacological manipulations.